The
double-stranded RNA-dependent
protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the
interferon (IFN)‑Stimulated Genes, PKR was initially recognized as an actor in the
antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of
eukaryotic initiation factor 2 (eIF2a). As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most
viral infections, indicating that PKR may play other roles in the cell other than just acting as an
antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter
protein and/or using its
kinase activity. Here we review the role of PKR as an eIF2a
kinase, its participation in the regulation of the
NF-kB, p38MAPK and
insulin pathways, and we focus on its role during
infection with the hepatitis C virus (HCV). PKR binds the HCV IRES
RNA, cooperates with some functions of the HCV core
protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter
protein and as an eIF2a-kinase, and in cooperation with the di-
ubiquitin-like protein ISG15. Developing
pharmaceutical inhibitors of PKR may help in resolving some
viral infections as well as stress-related damages.